(2006) report that the von Hippel-Lindau (VHL) protein is a positive regulator of p53, thus providing insight into the mechanisms by which VHL loss of function leads to cancer.
A subset of relevant clinically observed mutations to pVHL are thought to cause weaker binding of HIF-1α and are associated with cancer and cardiovascular diseases.
A suite of recent papers convincingly linking cilia to hedgehog signalling, platelet-derived growth factor signalling, Wnt signalling and the von Hippel-Lindau tumor suppressor protein has rapidly expanded the knowledge base connecting cilia to cancer.
According to in vitro and preclinical mouse studies, 2'-hydroxyflavanone can both protect the VHL locus and prevent the progression of VHL-mutant cancer.
Although missense mutations of the von Hippel-Lindau disease (VHL) gene are the most common germline mutation underlying this heritable cancer syndrome, the mechanism of tumorigenesis is unknown.
Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance.
HIF-stabilizing mutations have been detected in the von Hippel-Lindau (VHL) gene, as well as in other genes, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH) and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF2α itself: EPAS1<sup>HIF2α</sup> Importantly, the recent discovery of <i>EPAS1</i> mutations in PPGLs and the results of comprehensive <i>in vitro</i> and <i>in vivo</i> studies revealing their oncogenic roles characterized a hitherto unknown direct mechanism of HIF2α activation in human cancer.
However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors.
Human genetic studies have now shown that 25-30% of patients have hereditary PH due to a germline mutation in the SDHB, SDHD, VHL, RET or NF1 gene and that the identification of a germline SDHB mutation is associated with a high risk of malignancy and a poor prognosis in PH/PGL patients.3.
Identification of the mechanism of inactivation of the VHL gene, as well as the structure and function of the VHL gene product, ultimately may provide clinicians with greater understanding of this malignancy as well as with methods for earlier diagnosis.
Loss of von Hippel-Lindau (VHL) protein function results in an autosomal-dominant cancer syndrome known as VHL disease, which manifests as angiomas of the retina, hemangioblastomas of the central nervous system, renal clear-cell carcinomas and pheochromocytomas.
Mutation of the von Hippel-Lindau tumor suppressor gene (vhl) causes the von Hippel-Lindau cancer syndrome as well as sporadic renal clear cell carcinoma.
Mutations in the von Hippel-Lindau (VHL) gene are involved in the family cancer syndrome for which it is named and the development of sporadic renal cell cancer (RCC).
Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization.
Pheochromocytomas and paragangliomas are neuroendocrine tumors that occur in the context of inherited cancer syndromes in ∼30% of cases and are linked to germline mutations in the VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127 genes.
Pivotal for the understanding of the progression of malignancy of clear cell renal cell carcinomas are findings connecting its biology to inactivation of the von Hippel-Lindau tumour suppressor gene product (VHLp), found in most CC-RCCs.